The work proposed relates to the synthesis and pharmacological evaluation of new and optically pure antipsychotic (neuroleptic), antidepressant, antiparkinson, anticonvulsant and antihistaminic drugs. One of the synthetic schemes, discovered in our laboratories and outlined in this proposal, provides a simple method for the synthesis of many optically pure drugs in each of these categories. While we are interested in preparing compounds of clinical significance we also plan to study basic pharmacological mechanisms of action and stereostructure-action relationships. Since all drugs proposed to be synthesized are prepared from amino acids of known absolute configuration, the absolute configuration of the final drugs also will be known. Optical purity of intermediates and final products will be verified by ORD and/or CD analysis. These optically pure compounds will be evaluated by established methods for the above mentioned activities. Biological evaluation will include pharmacological testing in vivo and in vitro, behavioral and biochemical studies. Because of the facile syntheses described in this proposal we will be able to study many series of optically pure enantiomorphs both qualitatively and quantatively; the latter will employ the Hansch approach. Such an approach, heretofore, has never been possible with drugs of known configuration because of the difficulties involved in preparing many optically pure compounds by classical resolution methods. In addition to our primary interest in studying drugs useful for treating diseases of the central nervous system (psychosis, depression, Parkinson's disease and epilepsy) we will examine some selected antagonists on the H2 histamine receptor; i.e. histamine induced gastric acid secretion. Such antagonists have potential clinical significance in the therapeutic treatment of gastric ulcers. BIBLIOGRAPHIC REFERENCES: M.M. Faust, R.G. Rahwan, and D.T. Witiak, Prostaglandin antagonist activity of 2-substituted-3-dimethylamino-5, 6-methylene dioxyindenes. To be submitted (1976). D.T. Witiak, B.R. Vishnuvajjala, T.K. Gupta, and M.C. Gerald. 8-Chloro-S-and R-10-(S-and R-3' -methylethylaminopyrrolidino) -10, 11-dihydrodibenzo (b,f) thiepins. Synthesis and Pharmacological studies. J. Med. Chem. in press (Jan. 1976).